Total synthesis of galanthamine, analogues and derivatives thereof

ABSTRACT

The invention relates to a method for the synthesis of galanthamine, the derivatives and analogues thereof of formula (1) where R 1 =a hydrogen atom, R 2 =a hydroxy group, R 1  and R 2  together form ═O, R 3 , R 4 , and R 5  independently=a hydrogen atom, a hydroxy group or a (C 1 -C 2 )alkoxy group, R 6 ═H, (C 1 -C 12 )alkyl, (CH 2 ) n NR 7 R 8 , or —(CH 2 ) n N + R 7 R 8 R 9  where n=1 to 12, Z=two hydrogen atoms, or an oxygen atom and X=an oxygen, sulphur or nitrogen atom, or a —SO, —SO 2 , or —NR 6  group where R 6  is as defined above or is an amine protecting group.

The present patent application is a non-provisional application ofInternational Application No. PCT/FR02/02045, filed Jun. 14, 2002.

The present invention relates to a method of synthesizing galanthamine,its analogues, and its derivatives, and to the corresponding synthesisintermediates.

(−)-Galanthamine of formula (A)

is an alkaloid which is isolated from the family of the Amaryllidaceaeand acts as a competitive, selective, and reversible inhibitor ofacetylcholinesterase (Harvey A. L. (1995), Pharmac. Ther, 68, 113).

It has been used for a number of years in the treatment of myastheniaand in certain neurological diseases such as poliomyelitis, as ananticurare agent, and as a parasymphaticomimetic agent.

In particular this compound enhances the cognitive functions of personssuffering from Alzheimer's disease, which is characterized by damage tothe cholinergic neurotransmission (Weinstock M. (1999), CNS Drugs, 12,307). At present galanthamine is sold for this indication in Austria andSweden and should shortly be so sold in the other countries of Europeand in the United States.

(−)-Galanthamine may be extracted from a variety of plant sources, inparticular from Galanthus nivalis, G. narcissus, G. leucojum or G.crinium, but in very small quantities, which are inadequate forcommercial use.

Galanthamine was first synthesized by Barton D. H. R. et al. (J. Chem.Soc. (1962), 806), the key step of this method being the oxidativecyclization of the phenol, of which the yield is only 0.5%. Many groupshave attempted to improve the yields of this synthesis method so as toallow it to be used on the industrial scale; thus Czollner L. et al.(Tetrahedron Letters (1998), 39, 2087) obtained a yield of 45 to 50% andKrikorian et al. (Synthetic Communications (2000), 30 (16), 2833) yieldsof 60%. However, despite the increase in these yields, these methodsremain difficult to implement on the industrial scale.

Furthermore, a number of groups have attempted to develop syntheses ofgalanthamine, its analogues and derivatives by nonbiomimetic routes.

Thus the group of Ishisaki M. et al. (J. Org. Chem. (1993), 58, 3877)describes a synthesis by free-radical reaction of lycoramine, analkaloid from the galanthamine family. Following a retrosyntheticanalysis of lycoramine (1,2-dihydrogalanthamine), the authors show thatthe compound of structure (B)

is able to lead only to the total synthesis of lycoramine, in 3 stepswith an overall yield of 13%.

This intermediate therefore does not make it possible to obtaingalanthamine.

Galanthamine and its derivatives such as lycoramine are characterized bythe presence of a spiro quaternary carbon, the creation of which hasbeen found to be the limiting step in the total synthesis.

The inventors were the first to describe a new strategy to form thiscritical quaternary carbon in lycoramine (Gras E. et al., TetrahedronLetters (1999), 40, 9243), using an intramolecular Heck reaction; theysynthesized the intermediate of formula (C)

and used it to prepare lycoramine by introduction of an amine group,Pictet-Spengler cyclization, and reduction with LiAlH₄ intetrahydrofuran in accordance with the technique described by IshisakiM. (reference already cited).

More recently Trost B. M. et al. (J. Am. Chem. Soc. (2000), 122 (45),11262) have described the first full enantioselective synthesis of(−)-galanthamine without using the oxidative coupling of the phenol:they perform a cyclization by an intramolecular Heck reaction in thepresence of a bidentate alkylphosphine ligand and a palladium catalyst.

This synthesis, however, is made up of 15 steps and its overall yield is1%.

Pilger C. et al. (Synlett (2000), 8, 1163) and Parsons P. J. et al.(Tetrahedron Letters, (2001), 42, 2209) have likewise described newsynthetic pathways for the skeleton of 3-deoxygalanthamine, using aselective intramolecular Heck reaction as the key step. This approachdoes not allow creation of the allyl function, which is essential forthe biological activity.

In view of the importance of the market for galanthamine, itsderivatives, and its analogues, it is absolutely indispensable todevelop a synthesis which is easy, rapid, and economically viable.

The inventors have now found, surprisingly, that by using an oxidizingagent mixed with a support, and starting from the compound of formula(C) or an analogue, they obtained galanthamine or its derivatives inconditions which are compatible with an industrial utilization.

The invention accordingly provides a method of synthesizing compounds offormula (1)

in which

either R₁ represents a hydrogen atom and R₂ represents a hydroxyl group,or R₁ and R₂ together form ═O,

R₃, R₄ and R₅ represent each independently of one another a hydrogenatom, a hydroxyl group or a (C₁-C₁₂)alkoxy group,

R6 represents a hydrogen atom, a (C₁-C₁₂)alkyl group, a group—(CH²)_(n)NR₇R₈ or a group —(CH₂)_(n)N⁺R₇R₈R₉ where n=1 to 12, R₇ and R₈represent each independently of one another a hydrogen atom; a cyano;(C₁-C₄)alkyl; aryl(C₁-C₄)alkyl; aryl(C₁-C₄)alkenyl;(C₁-C₄)alkyl-carbonyl or arylcarbonyl radical; the alkyl, alkenyl, andaryl radicals being optionally substituted by one or more identical ordifferent radicals selected from halo, hydroxyl, alkoxy, alkylthio,acyl, free, salt-form or esterified carboxyl, cyano, nitro, mercapto oramino radicals, the amino radical being itself optionally substituted byone or more identical or different alkyl radicals; or R₇ and R₈ arelinked to each other and form, together with the nitrogen atom to whichthey are attached, a heterocycle; and R₉ represents a hydrogen atom or acyano, (C₁-C₄)alkyl, aryl(C₁-C₄)alkyl, aryl(C₁-C₄)alkenyl, alkylcarbonylor arylcarbonyl radical, the alkyl, alkenyl, and aryl radicals beingoptionally substituted by one or more identical or different radicalsselected from halo, hydroxyl, alkoxy, alkylthio, acyl, free, salt-formor esterified carboxyl, cyano, nitro, mercapto or amino radicals, theamino radical being itself optionally substituted by one or moreidentical or different alkyl radicals;

Z represents either two hydrogen atoms or one oxygen atom, and

X represents alternatively an oxygen atom or a sulfur atom or a nitrogenatom or an —SO group or an —SO₂ group or a group —NR₆ where R₆ is asdefined above or represents an amine-protective group,

characterized in that it comprises a step in which an α,β-ethylenicketone of formula (10)

is oxidized to a spirodienone of formula (11),

In one advantageous embodiment of the method the support is a mixture ofsilica and alumina.

In one particularly advantageous embodiment the mixture of silica andalumina is a 50/50 mixture.

In one preferred embodiment the oxidation is performed in the presenceof benzeneselinic anhydride mixed with a support, preferably aninorganic support. By way of example mention may be made in particularof molecular sieves whose size is preferably between 3 and 5 Å, andsilica/alumina mixtures.

The compounds of formula (1) are analogues and derivatives ofgalanthamine, particularly basic analogues of galanthamine in which thenitrogen atom of the ring D can be converted to its salt form, andanalogues containing an iminium function in the ring D, such as thosedescribed in international application WO 97/03987 and in the article byMary A. et al. (Bioorganic and Medicinal Chemistry (1988), 6, 1835).These compounds possess 3 asymmetric carbons and may therefore exist inthe form of pure stereoisomers or mixtures. Preferably the 3 carbon isof α configuration as in natural galanthamine.

In one advantageous embodiment of the method according to the inventiona derivative of formula (6)

in which Hal represents a halogen atom selected from bromine and iodineatoms, R₃, R₄, and R₅ are as defined in claim 1, and R₁₀ represents anamine group or a hydroxyl group is reacted with(1,4-dioxaspiro[4.5]dec-7-en-8-yl)acetic acid of formula (7),

and a compound of formula (8)

is obtained which is cyclized by an intramolecular Heck reaction to givea compound of formula (9)

the cyclization reaction is performed under conventional conditionsknown to the skilled worker, particularly in the presence of a palladiumcatalyst or a palladium(0) precursor catalyst, such as for exampletris(dibenzylideneacetone)dipalladium, and bidentate alkylphosphinederivatives such as for example 1,2-bis-(diphenylphosphino)ethane (dppe)or 1,2-bis(dicyclohexylphosphino)ethane (dcpe), and in a mixture ofthallium acetate and acetonitrile or dimethylacetamide; subsequently thedioxolane function of the compound of formula (9) is deprotected, in thepresence for example of a hydride acceptor such as, for example,tri-phenylcarbenium tetrafluoroborate or triphenylcarbeniumhexafluorophosphate, to give the α,β-ethylenic ketone of formula (10)

which is oxidized in the presence of benzeneseleninic anhydride, towhich a mixture, preferably 50/50, of silica and alumina has been added,to give a compound of formula (11)

in which R₃, R₄, and R₅ and X are as defined above; subsequently theamine group is introduced into said compound of formula (11) by openingthe lactone with an amine of formula NHR₆ where R₆ is as defined above;this reaction is accompanied by a spontaneous, Michael-type additionreaction of the intermediately generated phenol with the dienone toform, with a quantitative yield, the corresponding amide of formula (12)

in which R₃, R₄, R₆ and X are as defined above.

Subsequently, the amide of formula (12) is cyclized, for example by aPictet-Spengler-type reaction; said reaction may be performed in thepresence of paraformaldehyde and trifluoroacetic acid; this gives acompound of formula (1a)

whose diastereoselective reduction, for example with L-Selectride®,leads to the corresponding derivative of formula (1b)

which is itself reduced under conventional conditions to give the final,corresponding compound of formula (1c)

According to another embodiment of the invention, when it is desired toobtain optically active compounds of formula (1a) to (1c), the compound(12) or (1a) is subjected to resolution under conventional conditionsknown to the skilled worker, and the steps described above areconducted.

In one particularly advantageous embodiment of the invention the methodallows galanthamine to be obtained in the form of the racemate or of itsoptically pure isomers.

The method according to the invention allows galanthamine, itsanalogues, and its derivatives to be obtained within a reasonable numberof steps which are compatible with an industrial process.

The invention likewise provides compounds of formula (11) and (12)

in which R₃, R₄, R₅, R₆, and X are as defined above, which are useful assynthesis intermediates.

The invention further provides compounds of formula (8) and (9)

in which Hal, R₃, R₄, and R₅ are as defined above and X represents asulfur atom, a nitrogen atom, an —SO group, an —SO₂ group, a group —NR₆where R₆ is as defined above or represents an amine-protective group.

The examples which follow illustrate the invention, though withoutlimiting it.

EXAMPLE 1 Total Synthesis of Galanthamine

1.1 2-iodo-6-methoxyphenyl (1′,4′-dioxaspiro[4.5]dec-7′-en-8′-yl)acetate(8)

500 mg (2.52 mmol; 1.05 eq) of (1,4-dioxaspiro[4.5]dec-7-en-8-yl)aceticacid (7) in solution in 10 ml of CH₂Cl₂ at 0° C. are admixed graduallywith 970 mg (5.05 mmol; 2.10 eq) of EDC in solution in 30 ml of CH₂Cl₂,then with 308 mg (2.52 mmol; 1.05 eq) of demethylaminopyridine insolution in 10 ml of CH₂Cl₂. The reaction mixture is stirred at 0° C.for 15 minutes and then 600 mg (2.4 mmol; 1.00 eq) of2-iodo-6-methoxyphenol 6 in solution in 10 ml of CH₂Cl₂ are added. After5 hours of stirring at ambient temperature the reaction mixture ishydrolyzed and extracted with ethyl acetate (AcOEt). The organic phaseis washed with saturated aqueous sodium chloride solution, dried overmagnesium sulfate and evaporated under vacuum. The residue is purifiedby flash chromatography on silica gel (elution: heptane/AcOEt: 7/3) togive 825 mg (80%) of 2-iodo-6-methoxyphenyl(1′,4′-dioxaspiro[4.5]dec-7′-en-8′-yl)acetate 8 in the form of acolorless oil.

Elemental analysis: calculated for C₁₇H₁₉IO₅: C, 47.46; H, 4.45; O,18.59; found: C, 47.34; H, 4.45; O, 18.41.

IR (CHCl₃) ν (cm⁻¹): 1764 (C═O); 1586 (C═C); 1468 (Car-C); 1267 (Car-O);1117 (C—O)

MS (EI, m/z): 430 (M⁺.); 250 (M⁺.—C₁OH₁₂O₃); 180 (M⁺—C₇H₇IO₂)

¹H NMR (CDCl₃, 200 MHz) δ (ppm): 7.37 (1H, dd, J₄₋₃=6.0, J₄₋₅=3.0, H4);6.95-6.90 (2H, m, H3, H5); 5.67 (1H, broad s, H7′); 4.00 (4H, s, H2′,H3′); 3.80 (3H, s, OCH₃); 3.32 (2H, s, CH2); 2.47-2.33 (4H, m, H6′,H9′); 1.85 (2H, t, J=6.4, H10′)

¹³C NMR (CDCl₃, 75 MHz) δ (ppm): 168.4 (C═O); 152.2 (C6); 141.7 (C1);131.3 (C3); 130.1 (C8′); 128.2 (C5); 124.2 (C7′); 112.9 (C6) 107.4(C5′); 92.4 (C2); 64.8 (C2′, C3′); 56.2 (OCH3); 42.3 (CH2); 36.0 (C6′);31.5 (C10′); 28.4 (C9′)1.2 8-methoxy-3,4,4a,8a-tetrahydro-1′,4′-dioxaschromen-2-one-[4,8′]-dec-6′-ene (9)

39 mg (0.04 mmol; 0.1 eq) of tris(dibenzylideneacetone)dipalladium and33 mg (0.08 mmol; 0.2 eq) of 1,2-bis(diphenylphosphino)ethane insolution in 10 ml of MeCN are heated for 30 minutes at 90° C. 117 mg(0.44 mmol; 1.2 eq) of thallium acetate and 160 mg (0.37 mmol; 1.0 eq)of 2-iodo-6-methoxyphenyl (1′,4′-dioxaspiro[4.5]dec-7′-en-8′-yl)acetate(8) are then added to the reaction mixture. After 72 hours of stirringat 90° C. the reaction mixture is filtered over Celite and evaporatedunder reduced pressure.

Purification by chromatography on silica gel (elution: heptane/AcOEt:7/3) of the residue obtained gives 12.5 mg (67%) of8-methoxy-3,4,4a,8a-tetrahydro-1′,4′-dioxaspiro-chromen-2-one-[4,8′]-dec-6′-ene9, isolated in the form of a white powder.

m.p.: 101° C.

Elemental analysis: calculated for C₁₇H₁₈O₅: C, 67.54; H, 6.00; O,26.46; found: C, 67.37; H, 6.05; O, 26.46.

HRMS (CI, m/z): calculated for C₁₇H₁₉O₅ ⁺: 303.11543; found: 303.12277.

IR (CHCl₃) ν (cm⁻¹): 1766 (C═O); 1583 (C═C); 1481 (CAR-C); 1233 (Car-O);1090 (C—O)

MS (CI, m/z): 303 (MH⁺)

¹H NMR (CDCl₃, 200 MHz) δ (ppm): 7.08 (1H, dd, J₆₋₅=J₆₋₇=8.0, H6); 6.91(1H, dd, J₇₋₆=8.0, J₇₋₅=1.5, H7); 6.81 (1H, dd, J₅₋₆=8.0, J₅₋₇=1.5, H5);5.94 (1H, d, J₆₋₇=10.0, H6′); 5.68 (1H, d, J7′-6′=10.0, H7′); 4.05-3.97(4H, m, H2′, H3′); 3.90 (3H, s, OCH₃); 2.80 (1H, d, J_(gem)=15.4, H3);5.38 (1H, d, J_(gem)=15.4, H3); 1.95-1.76 (4H, m, H9′, H10′)

¹³C NMR (CDCl₃, 50 MHz) δ (ppm): 166.7 (C2); 148.6 (C8); 140.1 (C8a);134.8 (C6′); 131.4 (C7′); 128.6 (C4a); 124.1 (C5); 119.9 (C6) 112.4(C7); 105.8 (C5′); 65.9 (C2′, C3′); 60.1 (OCH3); 41.5 (C3); 39.0 (C4);32.8 (C10′); 30.4 (C9′)1.38-methoxy-3,4,4a,8a-tetrahydrospirochromen-2-one-[4,4′]-cyclohex-2′-en-1′-one(10)

1.10 g (3.68 mmol; 1.0 eq) of8-methoxy-3,4,4a,8a-tetrahydro-1′,4′-dioxaspirochromen-2-one-[4,8′]-dec-6′-ene(9) dissolved in 50 ml of anhydrous CH₂Cl₂ are admixed with 1.21 g (3.68mmol; 1.0 eq) of triphenyl-carbenium tetrafluoroborate. After 1 hour ofstirring at ambient temperature the reaction mixture is hydrolyzed withwater and then extracted with CH₂Cl₂. The organic phase is washed withsaturated aqueous sodium choride solution, dried over magnesium sulfateand evaporated under vacuum. Purification by flash chromatography onsilica gel (elution: heptane/AcOEt: 8/2 then 5/5) of the residueobtained gives 940 mg (100%) of8-methoxy-3,4,4a,8a-tetrahydrospirochromen-2-one-[4,4′]-cyclohex-2′-en-1′-one(10), isolated in the form of a white powder.

m.p.: 130° C.

Elemental analysis: calculated for C₁₅H₁₄O₄: C, 69.76; H, 5.46; O,24.78; found: C, 69.53; H, 5.61; O, 24.76.

IR(CHCl₃) ν (cm⁻¹): 1770 (C═O); 1680 (O—C═O); 1585 (Car-C); 1480(Car-C); 1248 (Car-O)

MS (CI, m/z): 259 (MH⁺)

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 7.13 (1H, dd, J₆₋₅=J₆₋₇=8.0, H6); 6.98(1H, dd, J₇₋₆=8.0, J₇₋₅=1.3, H7); 6.75 (1H, dd, J₅₋₆=8.0, J₅₋₇=1.3, H5);6.70 (1H, d, J_(3′-2′)=10.1, H3′); 6.30 (1H, d, J2′-3′=10.1, H2′); 3.92(3H, s, OCH3); 2.93 (1H, d, J_(gem)=15.5, H3); 2.86 (1H, d,J_(gem)=15.5, H3); 2.44 (2H, dd, J5′-6′=6.0, J_(gem)=12, H5′); 2.19 (2H,dd, J6′-5′=6.0, H6′)

¹³C NMR (CDCl₃, 75 MHz) δ (ppm): 198.7 (C1′); 165.4 (C2); 150.1 (C3′);148.9 (C8); 140.0 (C8a); 132.5 (C2′); 127.5 (C4a); 125.1 (C5) 118.3(C6); 112.7 (C7); 56.3 (OCH3); 40.4 (C3); 39.2 (C4); 34.7 (C6′); 33.5(C5′)1.48-methoxy-3,4,4a,8a-tetrahydro-spiro-chromen-2-one-[4,4′]-cyclohex-2′,5′-dien-1′-one(11)

125 mg (0.48 mmol; 1.0 eq) of8-methoxy-3,4,4a,8a-tetrahydro-spiro-chromen-2-one-[4,4′]-cyclohex-2′-en-1′-one(10) in solution in 12 ml of anhydrous chlorobenzene containing 400 mgof silica and 400 mg of alumina are admixed with 691 mg (1.92 mmol; 4.0eq) of benzeneselininic anhydride. After 24 hours of stirring at refluxthe reaction mixture is filtered on a frit, rinsed with MeOH andevaporated under reduced pressure. The residue is taken up in CH₂Cl₂ andthen washed with saturated aqueous sodium chloride solution. The organicphase is dried over magnesium sulfate and evaporated under vacuum.Purification by flash chromatography on silica gel (elution: heptanethen heptane/AcOEt: 5/5) of the residue obtained gives 62 mg (50%) of8-methoxy-3,4,4a,8a-tetrahydro-spiro-chromen-2-one-[4,4′]-cyclo-hex-2′,5′-dien-1′-one(11), isolated in the form of a yellow powder.

m.p.: 176-178° C.

HRMS (CI, m/z): calculated for C₁₅H₁₃O₄ ⁺: 257.08139; found 257.08132.

IR (CHCl₃) ν (cm⁻¹): 1776 (C═O ketone); 1671 (C═O lactone); 1631 (C═C);1281 (Car-O); 1179 (C—O)

MS (CI, m/z): 257 (MH⁺); 238 (MH⁺-H₂O): 229 (MH⁺—CO)

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 7.08 (1H, dd, J₆₋₅=J₆₋₇=8.1, H6); 6.96(1H, d, J₇₋₆=8.1, H7); 6.89 (2H, d, J_(3′-2′)=J_(5′-6′)=10.3, H3′, H5′);6.54 (1H, d, J₅₋₆=8.1, H5); 6.39 (2H, d, J_(2′-3′)=J_(6′-5′)=10.3, H2′,H6′); 3.90 (3H, s, OCH₃); 2.90 (2H, s, H3)

¹³C NMR (CDCl₃, 75 MHz) δ (ppm): 184.5 (C1′); 164.6 (C2); 148.4 (C8);148.1 (C3′, C5′); 140.8 (C8a); 130.0 (C2′, (C6′); 125.4 (C6); 123.1(C4a); 117.6 (C5); 113.0 (C7); 56.3 (OCH₃); 42.8 (C4); 38.5 (C3)1.54a,9b-Dihydro-6-methoxy-9b-{[N-methylamino)-carbonyl]methyl}-dibenzofuran-3-one(12)

122 mg (0.43 mmol; 1.0 eq) of8-methoxy-3,4,4a,8a-tetrahydro-spiro-chromen-2-one-[4,4′]-cyclohex-2′,5′-dien-1′-one(11) in solution in 15 ml of tetrahydrofuran are admixed with 0.13 ml(1.51 mmol; 3.5 eq) of methylamine in solution (40%) in water. After 20minutes of stirring at ambient temperature the reaction mixture iswashed with saturated aqueous sodium chloride solution and extractedwith CH₂Cl₂. The organic phase is washed with saturated aqueous sodiumchloride solution, dried over magnesium sulfate and evaporated undervacuum. Purification by flash chromatography on silica gel (elution:CH₂Cl₂/MeOH: 95/5) of the residue obtained gives 137 mg (100%) of4a,9b-dihydro-6-methoxy-9b-{[N-methylamino)carbonyl]methyl}dibenzofuran-3-one(12), isolated in the form of a yellow paste.

HRMS (CI, m/z): calculated for C₁₆H₁₈NO₄ ⁺: 288.12359; found: 288.12350.

IR (CHCl₃) ν (cm-′): 3461 (N—H); 1680 (C═O ketone) (C═O amide); 1620(C═C); 1282 (Car-O)

MS (EI, m/z): 287 (M⁺.); 214 (M⁺.—C₃H₆NO)

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 6.87 (3H, m, H7, H8, H9); 6.61 (1H, dd,J_(1-4a)=1.8, J₁₋₂=10.0, H1); 6.05 (1H, broad s, NH); 5.98 (1H, d,J₂₋₁=10.0, H2); 5.14 (1H, broad s, H4a); 3.85 (3H, s, OCH₃); 3.16 (1H,dd, J_(4-4a)=4.5, J_(gem)=17.5, H4); 3.06 (1H, dd, J4-4a=2.5,J_(gem)=17.5, H4); 2.91 (2H, d, J_(gem)=15.0, CH₂); 2.78 (3H, s, NCH₃);2.76 (3H, s, NCH₃)

¹³C NMR (CDCl₃, 75 MHz) δ (ppm): 195.8 (C3); 169.4 (C═O); 147.3 (C1);146.8 (C6); 145.0 (C9a); 131.8 (C5a); 127.0 (C2); 122.4 (Car); 115.0(Car); 112.5 (Car); 86.2 (C4a); 56.0 (OCH3); 47.7 (C9b); 43.4 (CH2);38.7 (C4); 26.4 (NCH₃)1.6 (±)-11-oxonarwedine or(±)-6-methoxy-10-methyl-galantham-1-ene-3,11-dione (1a)

90 mg (0.31 mmol; 1.0 eq) of4a,9b-dihydro-6-methoxy-9b-{[N-methylamino)carbonyl]methyl}-dibenzofuran-3-one(12) in solution in 10 ml of 1,2-dichloroethane are admixed with 38 mg(1.26 mmol; 4.0 eq) of paraformaldehyde and 0.3 ml (3.93 mmol; 12.5 eq)of trifluoroacetic acid. After 20 hours of stirring at 60° C. thereaction mixture is washed with saturated aqueous sodiumhydrogencarbonate solution and extracted with CH₂Cl₂. The organic phaseis washed with saturated aqueous sodium chloride solution, dried overmagnesium sulfate and evaporated under vacuum. Purification by flashchromatography on silica gel (elution: CH₂Cl₂/MeOH: 95/5) of the residueobtained gives 59 mg (63%) of (±)-11-oxo-narwedine (13), isolated in theform of a colorless paste.

HRMS (CI, m/z): calculated for C₁₇H₁₇NO₄ ⁺: 300.12359; found: 300.12366.

IR (CHC₁₃) ν (cm⁻¹): 1723 (C═O ketone); 1680 (C═O amide); 1641 (C═C);1509 (Car-C); 1285 (Car-O)

MS (CI, m/z): 300 (MH⁺)

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 6.75 (2H, s, H7, H8); 6.39 (1H, dd,J_(2-4a)=2.7, J₁₋₂=10.2, H1); 6.06 (1H, d, J₂₋₁=10.2, H2); 4.85 (1H, d,J_(4a-4)=2.7, H4a); 4.51 (1H, d, J_(gem)=16.2, H9); 4.41 (1H, d,J_(gem)=16.2, H9); 3.86 (3H, s, OCH₃); 3.17 (1H, dd, J_(4-4a)=2.7,J_(gem)=17.7, H4); 3.06 (3H, s, NCH₃); 3.03 (1H, d, J_(gem)=13.8, H12);2.96 (1H, d, J_(gem)=13.8, H12); 2.83 (1H, dd, J_(4-4a)=2.7,J_(gem)=17.7, H4)

¹³C NMR (CDCl₃, 75 MHz) δ (ppm): 193.7 (C3); 170.1 (C11); 147.6 (C6);144.8 (C1, C5a); 129.8 (C12b); 127.7 (C2); 124.9 (C8a); 120.3 (Car);112.7 (Car); 87.1 (C4a); 56.3 (OCH₃); 51.9 (C9); 43.8 (C12a); 40.5(C12); 36.4 (C4); 36.0 (NCH₃)1.7 (±)-11-oxo-galanthamine or(±)-6-methoxy-10-methyl-galantham-1-en-3α-ol-11-one (1b)

20 mg (0.07 mmol; 1.0 eq) of (±)-11-oxo-narwedine 13 in solution in 2 mlof THF are admixed with 0.10 ml (0.10 mmol; 1.5 eq) of L-Selectride® insolution (1M) in THF. After 1 hour of stirring at −78° C. the reactionmixture is quenched with methanol and then evaporated under reducedpressure. The residue is taken up in AcOEt and washed with saturatedaqueous sodium carbonate. solution. The organic phase is washed withsaturated aqueous sodium chloride solution, dried over magnesium sulfateand evaporated under vacuum. Purification by preparative plate (elution:CH₂Cl₂/MeOH: 95/5) of the residue obtained gives 18.5 mg (93%) of(±)-10-oxogalanthamine (14), isolated in the form of a white powder.

m.p.: 191-192° C.

HRMS (CI, m/a): calculated for C₁₇H₂₀NO₄ ⁺: 302.13924; found: 302.13923.

IR. (CHCl₃) ν (cm⁻¹): 3557 (O—H); 1641 (C═O) (C═C); 1509 (Car-C); 1284(Car-O)

MS (CI, m/z): 302 (MH⁺); 284 (M⁺-OH); 258 (M⁺-C₂H₅N)

¹H NMR (CDCl₃, 300 MHz) δ (ppm): 6.72 (2H, s, H7, H8); 6.04 (1H, dd,J₂₋₃=5.4, J₂₋₁=10.2, H2); 5.51 (1H, d, J₁₋₂=10.2, H1); 4.76 (1H, broadt, J_(4a-4)=1.8, H4a); 4.46 (1H, d, J_(gem)=15.9, H9); 4.34 (1H, d,J_(gem)=15.9, H9); 4.17 (1H, broad t, J₃₋₂=5.4, H3); 3.87 (3H, s, OCH₃);3.04 (3H, s, NCH₃); 2.81 (1H, d, J_(gem)=14.1, H12) 2.74 (1H, d,J_(gem)=14.1, H12); 2.68 (1H, dd, J₄₋₃=3.6, J_(gem)=15.9, H4); 2.40 (1H,broad s, OH); 2.11 (1H, ddd, J_(4-4a)=1

¹³C NMR (CDCl₃, 75 MHz) δ (ppm): 171.0 (C11); 146.7 (C6); 144.9 (C5a);132.2 (C12b); 128.4 (C1, C2); 125.2 (C8a); 120.2 (Car); 112.1 (Car);112.1 (Car); 88.4 (C4a); 61.6 (C3); 56.2 (OCH₃); 52.1 (C9); 43.4 (C12a);41.6 (C12); 36.0 (NCH₃); 29.3 (C4)1.8 (±)-galanthamine (1c)

6 mg (0.15 mmol; 5.5 eq) of lithium aluminum hydride in suspension in 5ml of DME are admixed dropwise at 0° C. with 9 mg (0.06 mmol; 1.0 eq) of(±)-11-oxogalanthamine (1c) dissolved in 5 ml of DME. After 12 hours ofstirring at 50° C. the reaction mixture is quenched with 10% sodiumdithionite solution and then filtered over Celite (chloroform elution).The filtrate obtained is washed with 10% aqueous sodium dithionitesolution and extracted with chloroform. The organic phase is washed withsaturated aqueous sodium chloride solution, dried over magnesium sulfateand evaporated under vacuum. Purification by preparative plate (elution:CH₂Cl₂/MeOH: 90/10) of the residue obtained gives 7 mg (80%) of(±)-galanthamine (1c), isolated in the form of a white, powder.

IR (CHCl3) ν (cm⁻¹): 3562 (O—H); 1626 (C═C); 1599 (Car-C); 1508 (Car-C);1280 (Car-O)

MS (CI, m/z): 287 (M⁺.); 270 (M⁺.-OH); 244 (M⁺.-C₂H₅N); 230 (M⁺.-C₃H7N);216 (M⁺.-C₄H₉N)

¹H NMR (CDCl₃, 250 MHz) 6 (ppm): 6.67 (1H, d, J₁₋₂=8.3, Har); 6.63 (1H,d, J₁₋₂=8.3, Har); 6.07 (1H, dd, J₁₋₃=1.0, J₁₋₂=10.3, H1); 6.01 (1H, dd,J₂₋₃=4.3, J₂₋₁=10.3, H2); 4.62 (1H, broad s, H4a); 4.14 (1H, broad t,J=5.0, H3); 4.11 (1H, d, J_(gem)=15.3, H9); 3.84 (3H, S, OCH₃); 3.70(1H, d, J_(gem)=15.3, H9); 3.30 (1H, td, J₁₁₋₁₂=1.5, J_(gem)=14.3, H11);3.07 (1H, dt, J₁₁₋₁₂=3.5, J_(gem)=14.3, H11); 2.69 (1H, dt,J_(4-4a)=2.0, J_(gem)=15.8, H4); 2.48 (1H, broad s, OH); 2.41 (3H, s,NCH₃); 2.12 (1H, dd, J₁₂₋₁₁=3.5, J_(gem)=13.5, H12); 2.01 (1H, ddd,J_(4-4a)=2.0, J₄₋₃=5.0, J_(gem)=15.8, H4); 1.59 (1H, ddd, J₁₂₋₁₁=1.5,J₁₂₋₁₁=3.5, J_(gem)=13.5, H9)

¹³C NMR (CDCl₃, 75 MHz) δ (ppm): 146.0 (C6); 144.3 (C5a); 133.2 (C12b);129.2 (C8a); 127.8 (C1); 127.0 (C2); 122.3 (C8); 111.4 (C7); 88.9 (C4a);62.2 (C3); 60.6 (C9); 56.1 (OCH₃); 53.9 (C11) 48.3 (C12a); 42.0 (NCH3);33.8 (C12); 30.1 (C4)

EXAMPLE 2 Total Synthesis of Azagalanthamine

2.12-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-N-(2′-iodo-6′-methoxyphenyl)acetamide(16)

A solution of (1,4-dioxaspiro[4.5]dec-7-en-8-yl) acetic acid (567 mg;2.86 mmol; 1 eq) (7) and 2-iodo-6-methoxyaniline (1 g; 2.86 mmol; 1 eq)in anhydrous dichloromethane (30 mL) is admixed with2-chloro-1-methylpyridinium iodide (1.46 g; 5.73 mmol; 2 eq) andtriethylamine (3.98 mL; 28.65 mmol; 10 eq). The reaction mixture isheated at reflux for 20 hours. After cooling and acidification with 1NHCl solution to pH=5-6, the mixture is extracted with dichloromethane.The organic phases are washed with saturated aqueous sodium chloridesolution, dried over magnesium sulfate and evaporated under vacuum.Purification by flash chromatography on silica gel (eluent:heptane/ethyl acetate 4/6) gives 1.10 g of2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-N-(2′-iodo-6′-methoxy-phenyl)acetamide(16) in the form of a yellow foam (yield: 90%).

Elemental analysis calculated for C₁₇H₂₀INO₄ (m.p.: 429.25) C: 47.57; H:4.70; N: 3.26; O: 14.91; found C: 47.39; H: 4.59; N: 3.01; O: 15.16.

IR (CHCl₃) ν (cm⁻¹): 3382 (N—H); 1687 (C═O)

MS (ES) m/z: 429.8 [M⁺H]⁺.

¹H NMR (CDCl₃; 300 MHz) δ (ppm): 7.43 (dd, J=8.0, J=1.2; 1H; H3′); 7.18(broad s; 1H; NH); 6.98 (t, J=8.0; 1H; H4′); 6.91 (dd, J=8.0, J=1.2; 1H;H5′); 5.72 (broad s, 1H; H4); 3.99 (s; 4H; Hdioxolane); 3.80 (s; 3H;OCH₃); 3.15 (s; 2H; H2); 2.45 (broad s; 1H; H8); 2.37 (broad s, 1H; H5);2.37 (broad s, 2H; H6); 1.85 (t, J=6.4; 2H; H7).

¹³C NMR (CDCl₃; 62.9 MHz) δ (ppm): 169.2 (C(O)NH); 155.5 (C6′); 132.9(C1′); 130.8 (C3′); 129.6 (C4′); 128.1 (C8); 124.9 (C7); 111.7 (C5′);107.7 (C5); 99.8 (C2′); 64.8 (Cdioxolane); 56.1 (OCH₃); 45.7 (C2); 35.9(C6); 38.2 (C4); 35.0 (C3).2.22-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-N-(2′-iodo-6′-methoxyphenyl)-N-methylacetamide(17)

A solution of2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-N-(2′-iodo-6′-methoxyphenyl)acetamide(16) (1.88 g; 4.39 mmol; 1 eq) in 150 mL of anhydrous tetrahydrofuran(THF) is admixed dropwise at 0° C. with a suspension of NaH (263 mg;10.98 mmol; 2.5 eq) in anhydrous THF (120 mL). After 15 minutes thereaction mixture is allowed to return to ambient temperature anddimethyl sulfate (1.04 mL; 0.2 mmol; 2.5 eq) is added. The reactionmixture is kept with stirring at ambient temperature for 2 hours andthen the reaction is stopped by adding saturated aqueous sodiumhydrogencarbonate solution. Following extraction with ether, the organicphases are washed with saturated aqueous sodium chloride solution, driedover magnesium sulfate and evaporated under vacuum. Purification byflash chromatography on silica gel (eluent: heptane/ethyl acetate 4/6)of the residue obtained allows 26.9 mg of the product2-(1,4-dioxaspiro-[4.5]dec-7-en-8-yl)-N-(2′-iodo-6′-methoxyphenyl)-N-methylacetamide(17) to be obtained in the form of a colorless oil (yield: 86%). The 1HNMR spectrum reveals that the product is a mixture of two rotamers inapproximately 1:4 proportion.

Elemental analysis calculated for C₁₈H₂₂INO₄ (m.p.: 443.28) C: 48.77; H:5.00; found: C 48.98; H: 4.88.

IR (CHCl₃) ν (cm⁻¹): 1652 (C═O); 1602 (C═C).

MS (ES) m/z: 443.9 [M⁺H]⁺.

¹H NMR (CDCl₃; 300 MHz) δ (ppm) for the majority rotamer: 7.44 (dd,J=8.0, J=1.3; 1H; H3′); 7.01 (t, J=8.0; 1H; H4′); 6.90 (dd, J=8.0,J=1.3; 1H; H5′); 5.06 (broad s; 1H; H7); 3.94 (s; 4H; Hdioxolane); 3.81(s; 3H; OCH₃); 3.08 (s; 3H; NCH3); 2.73-2.65 (AB system, Jab=15.0; 2H;H2a and H2b); 2.21 (broad s; 2H; H3); 2.19 (broad s; 2H; H6); 1.78 (m;2H; H4).

¹³C NMR (CDCl₃; 75.4 MHz) δ (ppm) for the majority rotamer: 171.3(C(O)NMe); 156.3 (C6′); 134.8 (C1′); 131.1 (C8); 131.0 (C3′); 130.7(C4′); 122.5 (C7); 111.7 (C5′); 107.9 (C5); 101.7 (C2′); 64.3(Cdioxolane); 55.9 (OCH3); 42.2 (C2); 35.8 (C6); 34.5 (NCH₃); 31.0 (C4);27.5 (C3).2.38-methoxy-1-methyl-3,9′,10′-dihydro-1H-1′,4′-dioxaspiroquinolin-2-one-[4,8′]-dec-6′-ene(18)

A solution of tris(dibenzylideneacetone)dipalladium (36.8 mg; 0.04 mmol;0.05 eq) and 1,2-bis(diphenylphosphino)ethane (32.1 mg; 0.08 mmol; 0.1eq) in anhydrous dimethylacetamide (10 mL) is kept with stirring atambient temperature for 15 minutes. A solution of2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-N-(2′-iodo-6′-methoxyphenyl)-N-methylacetamide(17) (357 mg; 0.81 mmol; 1 eq) and 1,2,2,6,6-pentamethylpiperidine (582μL; 3.22 mmol; 4 eq) in anhydrous dimethylacetamide (30 mL) is thenadded dropwise and the reaction mixture is heated at 110° C. for 23hours. After cooling to ambient temperature, addition of saturatedaqueous sodium hydrogencarbonate solution, and extraction with ethylacetate, the organic phases are washed with saturated aqueous sodiumchloride solution, dried over magnesium sulfate and evaporated undervacuum. After purification by flash chromatography on silica gel(eluent: heptane/ethyl acetate 4/6) 15.0 mg of the product8-methoxy-1-methyl-3,9′,10′-dihydro-1H-1′,4′-dioxaspiroquinolin-2-one-[4,8′]-dec-6′-ene(18) are obtained in the form of a pale yellow oil (yield: 80%).

HRMS (CI, m/z); calculated for C₁₈H₂₁NO₄ ⁺: 315.15; found: 315.14794.

IR (CHC₁₃) ν (cm⁻¹): 1659 (C═O lactam).

MS (ES) m/z: 316.2 [M⁺H]⁺; 338.2 [M⁺Na]⁺

¹H NMR (CDCl₃; 300 MHz) δ (ppm): 7.04 (t, J=8.0; 1H; H6); 6.88 (dd,J=8.0, J=1.3; 1H; H5); 6.82 (dd, J=8.0, J=1.3; 1H; H7); 5.88 (d, J=10.0;1H; H6′); 5.62 (d, J=10.0; 1H; H7′); 4.03-3.90 (m; 4H; Hdioxolane); 3.85(s; 3H; OCH3); 3.39 (s; 3H; NCH₃); 2.58-2.48 (AB system, Jab=15.0; 2H;H3a and H3b); 1.85-1.73 (m; 4H; H9′ and H10′).

¹³C NMR (CDCl₃; 75.4 MHz) δ (ppm): 170.1 (C(O)NMe); 150.4 (C8); 136.2(C7′); 135.0 (C8a); 130.5 (C6′); 130.2 (C4a); 124.8 (C6); 119.4 (C5);112.4 (C7); 105.3 (C5′); 64.8 and 64.6 (Cdioxolane); 56.2 (OCH₃); 44.0(C3); 39.2 (C4); 34.7 (NCH₃); 30.4 and 30.0 (C9′ and C10′).2.48-methoxy-1-methyl-3,4-dihydro-1H-quinolin-2-one-[4.4′]-cyclohex-5′-ene-1′-one(19)

1.10 g (3.49 mmol; 1.0 eq) of8-methoxy-1-methyl-3,9′,10′-dihydro-1H-1′,4′-dioxaspiroquinolin-2-one-[4,8′]-dec-6′-ene(18) dissolved in 60 ml of anhydrous CH₂Cl₁ are admixed with 1.15 g(3.49 mmol; 1.0 eq) of triphenylcarbenium tetrafluoroborate. After 1hour of stirring at ambient temperature the reaction mixture ishydrolyzed with water and then extracted with CH₂Cl₂. The organic phaseis washed with saturated aqueous sodium chloride solution, dried overmagnesium sulfate and evaporated under vacuum. Purification by flashchromatography on silica gel (elution: heptane/AcOEt: 4/6) of theresidue obtained gives 898.5 mg of8-methoxy-1-methyl-3,4-dihydro-1H-quinolin-2-one-[4.4′]-cyclohex-5′-en-1′-one(19), isolated in the form of a yellow foam (yield: 95%).

HRMS (CI, m/z): calculated for C₁₆H₁₇NO₃ ⁺: 271.12; found: 271.12114.

IR (CHCl₃) ν (cm⁻¹): 3000 (C—H); 1677 (C═O amide; C═O enone); 1370(C═C); 1262 (C—OMe); 1086 (C—H.Ar).

MS (EI) m/z: 271 [M⁺.].

¹H NMR (CDCl₃; 250 MHz) δ (ppm): 7.08 (q; J=8.4; J=7.6; 1H; H6); 6.96(q; J=8.4; J=1.4; 1H; H5); 6.77(q; J=7.6; J=1.4; 1H; H7); 6.63 (d;J=10.2; 1H; H5′); 3.88 (s; 3H; OCH3); 3.42 (s; 3H; NCH3); 2.68 (systemAB; 2H, H3a and H3b; Jab=15.1); 2.43 (m; 2H; H3′); 2.10 (t; J=6.9; 2H;H2′).

¹³C NMR (CDCl₃; 75.4 MHz) δ (ppm): 198.8 (C1′); 169.0 (C2); 152.4 (C5′);150.6 (C8); 132.6 (C8a); 131.1 (C6′); 130.1 (C4a); 125.1 (C6); 118.5(C7); 112.8 (C5); 56.1 (OCH₃); 43.0 (C3); 39.8 (C4); 34.7 (NCH₃); 33.8(C2′); 31.5 (C3′).2.58-methoxy-1-methyl-3,4-dihydro-1H-quinolin-2-one-[4.4′]-cyclohex-2′,5′-dien-1′-one(20)

120 mg (0.44 mmol; 1.0 eq) of8-methoxy-1-methyl-3,4-dihydro-1H-quinolin-2-one-[4.4′]-cyclohex-5′-ene-1′-one19 in solution in 10 ml of chlorobenzene containing 400 mg of aluminaand 400 mg of silica are admixed with 637 mg (1.77 mmol; 4.0 eq) ofbenzeneselinic anhydride. After 24 hours of stirring at reflux thereaction mixture is filtered on a frit, washed with MeOH and evaporatedunder reduced pressure. The residue is taken up in and extracted withCH₂Cl₂, the aqueous phase being saturated with sodium chloride. Theorganic phase is washed with saturated aqueous sodium chloride solution,dried over magnesium sulfate and evaporated under vacuum. Purificationby flash chromatography on silica gel (elution: heptane/ethyl acetate:3.5/6.5) of the residue obtained gives 73 mg of8-methoxy-1-methyl-3,4-dihydro-1H-quinolin-2-one-[4.4′]-cyclohex-2′,5′-dien-1′-one(20), isolated in the form of a yellow foam (yield: 61%).

Elemental analysis calculated for C16H15NO3 (m.p.: 269) C: 71.36; H:5.61; N: 5.20; O: 17.82; found: C: 69.33; H: 5.58; N: 5.19; O: 17.38.

IR (CHCl₃) ν (cm⁻¹): 2962 (C—H); 1669 (C═O_(amide); C═O_(dienone)); 1600(C═C); 1370 (C—N); 1261 (C—OCH₃); 1097 (C—H.Ar).

MS (EI) m/z: 269 [M⁺.].

¹H NMR (CDCl₃; 300 MHz) δ (ppm): 7.06 (q; J=7.9; J=8.1; 1H; H6); 6.95(q; J=8.3; J=1.3; 1H; H7); 6.89 (d; J=9.8; 2H; H3′ and H5′); 6.65 (q;J=1.0; J=7.6; 1H; H5); 6.37 (d; J=9.8; 2H; H2′ and H6′); 3.88 (s; 3H;OCH₃); 3.47 (s; 3H; NCH₃); 2.70 (s; 2H; H3).

¹³C NMR (CDCl₃; 75.4 MHz) δ (ppm): 185.0 (C1′); 168.2 (C2′); 150.4 (C8);149.0 (C3′/C5′); 130.4 (C4a); 129.8 (C2′/C6′); 129.3 (C8a); 125.5 (C6);118.2 (C5); 113.3 (C7); 56.0 (OCH₃); 43.5 (C3); 34.7 (NCH₃).

2.6 (±)-11-oxoazanarwedine(21)

This compound is prepared from8-methoxy-1-methyl-3,4-dihydro-1H-quinolin-2-one-[4.4′]-cyclohex-2′,5′-dien-1′-one(20) in accordance with the procedure described in steps 1.5 and 1.6 ofexample 1.

2.7 (±)azagalanthamine (22)

This compound is obtained from (21) in accordance with the proceduredescribed in steps 1.7 and 1.8 of example 1.

1. A method of synthesizing compounds of formula (1)

in which either R₁ represents a hydrogen atom and R₂ represents a hydroxyl group, or R₁ and R₂ together form═O, R₃, R₄ and R₅ represent each independently of one another a hydrogen atom, a hydroxyl group or a (C₁-C₁₂)alkoxy group, R₆ represents a hydrogen atom, a (C₁-C₁₂)alkyl group, a group —(CH₂)_(n)NR₇R₈ or a group —(CH₂)_(n)N⁺R₇R₈R₉ where n=1 to 12, R₇ and R₈ represent each independently of one another a hydrogen atom; a cyano; (C₁-C₄)alkyl; aryl(C₁-C₄)alkyl; aryl(C₁-C₄)alkenyl; (C₁-C₄)alkyl-carbonyl or arylcarbonyl radical; the alkyl, alkenyl, and aryl radicals being optionally substituted by one or more identical or different radicals selected from halo, hydroxyl, alkoxy, alkylthio, acyl, free, salt-form or esterified carboxyl, cyano, nitro, mercapto or amino radicals, the amino radical being itself optionally substituted by one or more identical or different alkyl radicals; and R₉ represents a hydrogen atom or a cyano, (C₁-C₄)alkyl, aryl(C₁-C₄)alkyl, aryl (C₁-C₄)alkenyl, alkylcarbonyl or arylcarbonyl radical, the alkyl, alkenyl, and aryl radicals being optionally substituted by one or more identical or different radicals selected from halo, hydroxyl, alkoxy, alkylthio, acyl, free, salt-form or esterified carboxyl, cyano, nitro, mercapto or amino radicals, the amino radical being itself optionally substituted by one or more identical or different alkyl radicals; Z represents either two hydrogen atoms or one oxygen atom, and X represents alternatively an oxygen atom or a sulfur atom on an —SO group or an —SO₂ group or a group —NR₆ where R₆ is as defined above or represents an amine-protective group, comprising providing an α,β-ethylenic ketone of formula (10)

and oxidizing said ketone to a spirodienone of formula (11)

wherein said spirodienone of formula (11) is thereafter transformed to produce a compound of formula (1).
 2. A method according to claim 1, characterized in that the oxidation is performed in the presence of benzeneselininic anhydride and a support.
 3. A method according to claim 2, characterized in that the support is selected from the group consisting of molecular sieves and mixtures of silica and alumina.
 4. A method according to claim 3, characterized in that the mixture of silica and alumina is a 50/50 mixture.
 5. A method according to claim 1, characterized in that a compound of formula (6)

in which Hal represents a halogen atom selected from bromine and iodine atoms, R₃, R₄, and R₅ are as defined in claim 1, and R₁₀ represents an amine group or a hydroxyl group is reacted with (1,4-dioxaspiro[4.5]dec-7-en-8-yl)acetic acid of formula (7),

and a compound of formula (8)

is obtained which is cyclized by an intramolecular Heck reaction to give a compound of formula (9)

in the presence of a palladium or a palladium(0) precursor catalyst and of bidentate alkylphosphine ligands in a solvent, then the dixolane function of the compound of formula (9) is deprotected to give the α,β-ethylenic ketone of formula (10)

which is oxidized in the presence of benzeneseleninic anhydride, to which a mixture of silica and alumina has been added, to give a compound of formula (11)

which is reacted with an amine of formula NHR₆ where R₆ is as defined in claim 1 to give, by opening of the lactone, the corresponding amide of formula (12)

which is cyclized to give a compound of formula (1a),

which is optionally subjected to a diastereoselective reduction to give the corresponding derivative of formula (1b),

whose amide function can optionally be reduced to give a compound of formula (1c)


6. A method according to claim 5, characterized in that the compound of formula (12) is resolved and then the synthesis is continued to give the compounds of formula (1a) to (1c) in their optically active forms.
 7. A method according to claim 5, characterized in that the compound of formula (1a) is resolved and then the synthesis is continued to give the compounds of formula (1b) to (1c) in their optically active forms.
 8. A method according to claim 1, characterized in that galanthamine is prepared in the form of the racemate or of its optically pure isomers.
 9. Compound of formula (11)

in which R₃, R₄ and R₅ represent each independently of one another a hydrogen atom, a hydroxyl group or a (C₁-C₁₂)alkoxy group and X represents alternatively an oxygen atom or a sulfur atom or an —SO group or an —SO₂ group or a group —NR₆ where R₆ represents a hydrogen atom, a (C₁-C₁₂)alkyl group, a group —(CH₂)_(n)NR₇R₈ or a group —(CH₂)_(n)N⁺R₇R₈R₉ where n=1 to 12, R₇ and R₈ represent each independently of one another a hydrogen atom; a cyano; (C₁-C₄)alkyl; aryl(C₁C₄)alkyl; aryl(C₁-C₄)alkenyl; (C₁-C₄)alkyl-carbonyl or arylcarbonyl radical; the alkyl, alkenyl, and aryl radicals being optionally substituted by one or more identical or different radicals selected from halo, hydroxyl, alkoxy, alkylthio, acyl, free, salt-form or esterified carboxyl, cyano, nitro, mercapto or amino radicals, the amino radical being itself optionally substituted by one or more identical or different alkyl radicals; or represents an amine-protective group.
 10. Compounds according to claim 9, characterized in that R₃=OCH₃, R₄=R₅=H and X=O, NH or N—CH₃.
 11. Compound of formula (8)

in which Hal represents a halogen atom selected from bromine and iodine atoms, and R₃, R₄, and R₅ represent each independently of one another a hydrogen atom, a hydroxyl group or a (C₁-C₁₂)alkoxy group; and X represents alternatively an oxygen atom or a sulfur atom or a nitrogen atom or an —SO group, an —SO₂ group or a group —NR₆ where R₆ represents a hydrogen atom, a (C₁-C₁₂)alkyl group, a group —(CH₂)_(n)NR₇R₈ or a group —(CH₂)_(n)N⁺R₇R₈R₉ where n=1 to 12, R₇ and R₈ represent each independently of one another a hydrogen atom; a cyano; (C₁-C₄)alkyl; aryl(C₁-C₄)alkyl; aryl(C₁-C₄)alkenyl; (C₁-C₄)alkyl-carbonyl or arylcarbonyl radical; the alkyl, alkenyl, and aryl radicals being optionally substituted by one or more identical or different radicals selected from halo, hydroxyl, alkoxy, alkylthio, acyl, free, salt-form or esterified carboxyl, cyano, nitro, mercapto or amino radicals, the amino radical being itself optionally substituted by one or more identical or different alkyl radicals; or represents an amine-protective group.
 12. Compounds according to claim 11, characterized in that Hal=I, R₃=OCH₃, R₄=R₅=H and X=NH or N—CH₃.
 13. Compound of formula (12)

in which R₃, R₄ and R₅ represent each independently of one another a hydrogen atom, a hydroxyl group or a (C₁-C₁₂)alkoxy group; and R₆ represents a hydrogen atom, a (C₁-C₁₂)alkyl group, a group —(CH₂)_(n)NR₇R₈ or a group —(CH₂)_(n)N⁺R₇R₈R₉ where n=1 to 12, R₇ and R₈ represent each independently of one another a hydrogen atom; a cyano; (C₁-C₄)alkyl; aryl(C₁-C₄)alkyl; aryl(C₁-C₄)alkenyl; (C₁-C₄)alkyl-carbonyl or arylcarbonyl radical; the alkyl, alkenyl, and aryl radicals being optionally substituted by one or more identical or different radicals selected from halo, hydroxyl, alkoxy, alkylthio, acyl, free, salt-form or esterified carboxyl, cyano, nitro, mercapto or amino radicals, the amino radical being itself optionally substituted by one or more identical or different alkyl radicals; and X represents alternatively an oxygen atom or a sulfur atom or an —SO group or an —SO₂ group or a group —NR₆ where R₆ is as defined above or represents an amine-protective group.
 14. Compound of formula (9)

in which Hal, R₃, R₄, and R₅ are as defined in claim 1 and X represents alternatively an oxygen atom or sulfur atom or a nitrogen atom or an —SO group, an —SO₂ group or a group —NR₆ where R₆ represents a hydrogen atom, a (C₁-C₁₂)alkyl group, a group —(CH₂)_(n)NR₇R₈ or a group —(CH₂)_(n)N⁺R₇R₈R₉ where n=1 to 12, R₇ and R₈ represent each independently of one another a hydrogen atom; a cyano; (C₁-C₄)alkyl; aryl(C₁-C₄)alkyl; aryl(C₁-C₄)alkenyl; (C₁-C₄)alkyl-carbonyl or arylcarbonyl radical; the alkyl, alkenyl, and aryl radicals being optionally substituted by one or more identical or different radicals selected from halo, hydroxyl, alkoxy, alkylthio, acyl, free, salt-form or esterified carboxyl, cyano, nitro, mercapto or amino radicals, the amino radical being itself optionally substituted by one or more identical or different alkyl radicals; or represents an amine-protective group.
 15. The process of claim 2 wherein said support is an inorganic support.
 16. A compound according to claim 11 as follows:


17. A compound according to claim 14 as follows: 